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Neurobiological Principles Applied to the Rehabilitation of Stroke Patients

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00715520
First Posted: July 15, 2008
Last Update Posted: October 16, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Cathrin Buetefisch, Emory University
  Purpose
The purpose of this study is to use (Transcranial Magnetic Stimulation) TMS or drugs to improve learning of movement skills and the adaptation processes in patients after stroke. Once investigators have determined the improving effect of TMS and the drugs on learning of movement skills, the study team may be able to provide information that improves rehabilitative treatment and helps to improve recovery after stroke.

Condition Intervention
Stroke Other: Transcranial Magnetic Stimulation (TMS) Drug: Carbidopa-Levodopa Drug: Methylphenidate Drug: Amphetamine Sulfate Drug: Placebo Other: Sham Transcranial Magnetic Stimulation (TMS) Other: Transcranial Magnetic Stimulation (TMS) Training

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Neurobiological Principles Applied to the Rehabilitation of Stroke Patients

Resource links provided by NLM:


Further study details as provided by Cathrin Buetefisch, Emory University:

Primary Outcome Measures:
  • Aim 1: Mean Parameter Estimate for Maximal Motor Evoked Potential (MEPmax) Derived From Stimulus Response Curves (SRC) [ Time Frame: Baseline, Post-Training 1 (Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes) ]
    Motor evoked potential (MEP) amplitudes were measured prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2), and 60 minutes after the treatment (post-training 3).The MEP is elicited by transcranial magnetic stimulation (TMS) at increased intensity. Its amplitude is measured from peak to peak and expressed in millivolts (mV). Measured MEP amplitudes were plotted against the intensity to create a stimulus response curve (SRC). SRCs were modeled by a 3- parameter sigmoid function and MEPmax was extracted. Long-lasting increases in MEP amplitude indicate increases in motor cortex excitability and are associated with motor learning.

  • Aim 1: Mean Peak Acceleration of Wrist Extension Movements [ Time Frame: Baseline, Post-Training 1 (Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes) ]
    Mean peak acceleration was measured across study drug conditions prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2) and 60 minutes after the treatment (post-training 3). Increases in the mean peak acceleration of the trained wrist extension movements indicate motor learning. Acceleration was measured in g; a symbol for the average acceleration produced by gravity at the Earth's surface.


Secondary Outcome Measures:
  • Aim 2: Mean Sum of Normalized Motor Evoked Potentials (MEPs) With Respect to Pulse [ Time Frame: Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes) ]
    Mean sum of normalized MEP for repeated TMS (rTMS) conditions with respect to the pulse (-100, +300, placebo, zero) prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2) and 60 minutes after the treatment (post-training 3). Its amplitude is measured from peak to peak and expressed in mV. Long- lasting increases in MEP amplitude indicate increases in motor cortex excitability and are associated with motor learning.

  • Aim 2: Mean Peak Acceleration of Wrist Extension Movements With Respect to Pulse [ Time Frame: Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes) ]
    Mean peak acceleration of wrist movements for repeated TMS (rTMS) conditions with respect of the TMS pulse (-100, +300, placebo, zero) prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2) and 60 minutes after the treatment (post-training 3). Increases in the mean peak acceleration of the trained wrist extension movements indicate motor learning. Acceleration was measured in g; a symbol for the average acceleration produced by gravity at the Earth's surface.

  • Aim 2: Mean Sum of Normalized Motor Evoked Potentials (MEPs) for rTMS Treatment With Respect to Frequency [ Time Frame: Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes) ]
    Mean sum of normalized MEP for the different frequencies of rTMS treatment (placebo at 0.1 Hz, 0.1 Hz, 0.25 Hz, 0.5 Hz) prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2) and 60 minutes after the treatment (post-training 3). Increases in the mean peak acceleration of the trained wrist extension movements indicate motor learning.

  • Aim 2: Mean Peak Acceleration for rTMS Treatment With Respect to Frequency [ Time Frame: Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes) ]
    Mean peak acceleration for the different frequencies of rTMS treatment (placebo, 0.1 Hz, 0.25 Hz, 0.5 Hz) prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2) and 60 minutes after the treatment (post-training 3). Increases in the mean peak acceleration of the trained wrist extension movements indicate motor learning. Acceleration was measured in g; a symbol for the average acceleration produced by gravity at the Earth's surface.

  • Aim 3: Mean Parameter Estimate for Maximal Motor Evoked Potential (MEPmax) Derived From Stimulus Response Curves (SRC) [ Time Frame: Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes) ]
    Motor evoked potential (MEP) amplitudes were measured prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2), and 60 minutes after the treatment (post-training 3).The MEP is elicited by transcranial magnetic stimulation (TMS) at increased intensity. Its amplitude is measured from peak to peak and expressed in millivolts (mV). Measured MEP amplitudes were plotted against the intensity to create a stimulus response curve (SRC). SRCs were modeled by a 3- parameter sigmoid function and MEPmax was extracted. Long-lasting increases in MEP amplitude indicate increases in motor cortex excitability and are associated with motor learning.

  • Aim 3: Mean Peak Acceleration of Wrist Extension Movements [ Time Frame: Baseline, Post-Training 1(Immediately), Post-Training 2 (30 Minutes), Post-Training 3 (60 Minutes) ]
    Mean peak acceleration was measured across study drug conditions prior to treatment (baseline), immediately after the treatment (post-training 1), 30 minutes after the treatment (post-training 2) and 60 minutes after the treatment (post-training 3). Increases in the mean peak acceleration of the trained wrist extension movements indicate motor learning. Acceleration was measured in g; a symbol for the average acceleration produced by gravity at the Earth's surface.


Enrollment: 33
Study Start Date: April 2007
Study Completion Date: September 2016
Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Aim 1
Healthy adult female and male subjects will receive study drugs and TMS training to measure M1 excitability.
Drug: Carbidopa-Levodopa

Participants will receive one oral dose of carbidopa-levodopa 25mg one hour prior to measuring wrist extension movements.

The order in which Carbidopa-Levodopa is given will be randomized per participant.

Other Name: Sinemet
Drug: Methylphenidate

Participants will receive one oral dose of methylphenidate 40mg 2 hours prior to measuring wrist extension movements.

The order in which Methylphenidate is given will be randomized per participant.

Drug: Amphetamine Sulfate

Participants will receive one oral dose of amphetamine sulfate 10mg 2 hours prior to measuring wrist extension movements.

The order in which Amphetamine Sulfate is given will be randomized per participant.

Drug: Placebo

Participants will receive one oral tablet of placebo 2 hours prior to measuring wrist extension movements.

The order in which Placebo is given will be randomized per participant.

Other: Transcranial Magnetic Stimulation (TMS) Training
TMS surface electromyographic activity will be recorded with surface electrodes mounted on the skin overlaying a forearm muscle. Single pulses of TMS at increasing intensity will be delivered to measure motor cortex excitability. Peak acceleration and TMS evoked responses in the muscle will be measured prior to the training, after completion of the training and again one hour after completion of the training.
Experimental: Aim 2
Healthy adult female and male subjects will receive repetitive TMS (rTMS) at different times or frequencies with respect to the training movement or sham stimulation.
Other: Transcranial Magnetic Stimulation (TMS)
Each TMS training session will begin with a baseline measurement lasting about 30 minutes in which brief magnetic pulses will be generated by the single—pulse and paired pulse TMS stimulator and the responses are recorded with surface EMG electrodes. Participants will be instructed to move their wrist for up to ½ hour. After these measures, rTMS will be applied to the scalp during training. Stimulation will occur at a low rate of different frequencies and different times with respect to the training movement depending on the experimental condition. In the last phase of the session post—training measurements will be done using single TMS pulses. TMS pulses and intensity with be given in random order.
Other: Sham Transcranial Magnetic Stimulation (TMS)
Sham TMS pulses will be randomly administered during TMS sessions.
Experimental: Aim 3
Female and male subjects who have experienced a cerebral ischemic infarction, will receive study drugs and TMS to measure M1 excitability.
Drug: Carbidopa-Levodopa

Participants will receive one oral dose of carbidopa-levodopa 25mg one hour prior to measuring wrist extension movements.

The order in which Carbidopa-Levodopa is given will be randomized per participant.

Other Name: Sinemet
Drug: Methylphenidate

Participants will receive one oral dose of methylphenidate 40mg 2 hours prior to measuring wrist extension movements.

The order in which Methylphenidate is given will be randomized per participant.

Drug: Amphetamine Sulfate

Participants will receive one oral dose of amphetamine sulfate 10mg 2 hours prior to measuring wrist extension movements.

The order in which Amphetamine Sulfate is given will be randomized per participant.

Drug: Placebo

Participants will receive one oral tablet of placebo 2 hours prior to measuring wrist extension movements.

The order in which Placebo is given will be randomized per participant.

Other: Sham Transcranial Magnetic Stimulation (TMS)
Sham TMS pulses will be randomly administered during TMS sessions.
Other: Transcranial Magnetic Stimulation (TMS) Training
TMS surface electromyographic activity will be recorded with surface electrodes mounted on the skin overlaying a forearm muscle. Single pulses of TMS at increasing intensity will be delivered to measure motor cortex excitability. Peak acceleration and TMS evoked responses in the muscle will be measured prior to the training, after completion of the training and again one hour after completion of the training.

Detailed Description:
Previous studies have shown, that when patients learn a new motor movement, it may cause a change in the way the nerves act in the area of the brain that controls movement. This change is called use-dependent plasticity. The ability of that part of the brain, called the motor cortex (M1), to reorganize plays a major role in the recovery of motor deficits post-stroke; hence the importance for further development of rehabilitative strategies that utilize this potential for recovery. In this proposed study, investigators will further examine influences of use-dependent plasticity in the non-injured M1 of healthy subjects and injured M1 of stroke subjects using a combination of non-invasive cortical stimulation, medication, and exercise techniques. In Aim 1, investigators will test the effect of drugs that interact specifically with different neurotransmitter systems on use-dependent plasticity in intact M1 of healthy humans. In Aim 2, investigators will identify the parameters for non-invasive transcranial magnetic stimulation (TMS) of M1 that are most effective to enhance use-dependent plasticity in intact healthy human M1. In Aim 3, investigators will test the drugs and rTMS protocols that were demonstrated to be most effective to enhance use- dependent plasticity in the Specific Aim 1 and 2 and apply them to participants who have experienced a stroke. Results from this study will help to inform future research about the efficacy of plasticity enhancing methods in injured M1 of stroke patients.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Aims 1 and 2

Inclusion Criteria:

  • Normal neurological examination
  • Ability to meet criteria of inclusion experiment
  • Ability to give informed consent.

Exclusion Criteria:

  • History or neurological or psychiatric disease
  • Abnormal MRI of brain
  • Abnormal neuropsychological testing
  • Intake of CNS active drugs
  • History of seizure disorder
  • History of migraine headaches
  • History of anaphylaxis or allergic reactions
  • Contraindication to TMS

Aim 3:

Inclusion Criteria:

  • Cerebral ischemic infarction more than 6 months prior to entering the study
  • Single lesion as defined by MRI of the brain affecting the primary motor output system of the hand at a cortical (M1) level or subcortical level, or unilateral, and supratentorial in absence of history of a previous symptomatic stroke within 3 months of the current stroke
  • Dense paresis of the hand for more than three days after cerebral infarction (MRC of < 4- of wrist- and finger extension/flexion movements)
  • Good functional recovery of hand function as defined by MRC of 4 or 4+ of wrist- and finger extension/flexion movements
  • Ability to perform wrist extension movements
  • Ability to meet criteria of inclusion experiment
  • Ability to give informed consent
  • Ability of TMS to elicit a measurable MEP of > 100 μV and an increase in MEP amplitude with increasing stimulus intensity (up to 100% of MSO) of at least 20% over MEP amplitude at MT

Exclusion Criteria:

  • History or neurological or psychiatric disease, including bipolar disorder
  • Intake of CNS active drugs
  • History of seizure disorder
  • History of migraine headaches
  • History of anaphylaxis or allergic reactions
  • Contraindication to TMS
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00715520


Locations
United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States, 30322
Sponsors and Collaborators
Emory University
National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
Principal Investigator: Cathrin M Buetefisch, MD Emory University
  More Information

Responsible Party: Cathrin Buetefisch, Dr. Cathrin Buetefisch, Emory University
ClinicalTrials.gov Identifier: NCT00715520     History of Changes
Other Study ID Numbers: IRB00046953
R01NS060830-01A1 ( U.S. NIH Grant/Contract )
NPARR01 ( Other Identifier: Other )
First Submitted: July 11, 2008
First Posted: July 15, 2008
Results First Submitted: October 12, 2017
Results First Posted: October 16, 2017
Last Update Posted: October 16, 2017
Last Verified: October 2017

Keywords provided by Cathrin Buetefisch, Emory University:
Transcranial Magnetic Stimulation
Rehabilitation
Stroke
Plasticity

Additional relevant MeSH terms:
Stroke
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Methylphenidate
Amphetamine
Levodopa
Carbidopa
Carbidopa, levodopa drug combination
Central Nervous System Stimulants
Physiological Effects of Drugs
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Dopamine Agents
Neurotransmitter Agents
Antiparkinson Agents
Anti-Dyskinesia Agents
Aromatic Amino Acid Decarboxylase Inhibitors
Enzyme Inhibitors
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Adrenergic Agents
Adrenergic Uptake Inhibitors
Adjuvants, Immunologic